DESCRIPTION (Applicant's abstract): An important therapeutic issue in neuropsychiatric disease, particularly in geriatric patients, is the variability in treatment response and the inability to predict treatment outcome. Decreased monoaminergic responsiveness may be a potential neurobiologic mechanism underlying treatment resistance across several neuropsychiatric disorders. The overarching theme of the candidate's funded research in AD, schizophrenia and geriatric depression is that decreased monoaminergic responsiveness is related to treatment resistance. To evaluate monoaminergic function in vivo, the candidate has developed methods using Positron Emission Tomography (PET) imaging, radiotracers for neurotransmitter receptors and pharmacologic challenges. This application of PET methodology represents the most direct, non-invasive and quantitative method of measuring neurotransmitter activity in the living human brain. The PET studies performed thus far have consistently demonstrated substantial between subject variability in monoamine responsiveness in normal controls and in patients. Variability of monoamine responsiveness has been observed also in pharmacologic challenge studies using behavioral and neuroendocrine outcome measures. The goals of this Independent Scientist Award are to obtain training in methods complementary to brain imaging techniques that will enable the candidate to better interpret the variability in monoaminergic responsiveness observed in the PET data. The goals of the training experience are to incorporate genetic markers of monoamine receptor and transporter alleles and polysomnographic methods into her existing research program and to obtain training in the neuroanatomy of cholinergic and monoaminergic interactions and neuroimaging in affective disorders. The research plan is conducted within the framework of three funded studies to use PET to investigate 1) serotonin-dopamine interactions in schizophrenia; 2) cholinergic modulation of monoamine function in Alzheimer's Disease; and 3) the effects of sleep deprivation and antidepressant treatment on cerebral glucose metabolism in geriatric depression. These studies are designed to relate alterations in monoamine responsiveness to subsequent therapeutic response. The long term goal of the candidate's research is to understand the neurobiologic substrates of treatment resistance in neurodegenerative disorders and to use the genetic, polysomnographic and imaging data to predict the course of pharmacotherapy. The Independent Scientist Award will enable the candidate to firmly focus her research in the area of geriatric neuropsychiatry.